Approximately 98 percent of cases of acute promyelocytic leukemia (APL) are associated with a specific t(15;17) chromosomal translocation that fuses the Retinoic Acid Receptor alpha (RARa) gene locus to the Promyelocytic Leukemia (PML) gene locus. The resulting PML-RARa fusion protein is necessary for leukemogenesis and confers retinoic acid responsiveness to leukemic cells. Treatment with retinoic acid results in differentiation of leukemic cells and clinical remission in APL patients. However, 15-20 percent of patients relapse, often necessitating autologous bone marrow transplantation that may further contribute to relapse due the presence of leukemic cells in the transplant. We propose to develop gene therapy for APL by combining lentiviral vector systems with the method of gene silencing by RNA interference (RNAi). The specific aims are: (1) Development of a lentiviral vector that delivers RNAi to downregulate expression of the PML-RARa fusion protein; and (2) Evaluation of lentiviral vector-mediated RNAi against PML-RARa in a mouse model of APL. Leukemic bone marrow cells will be transduced with lentiviral vectors prior to transplantation. Recipient mice will be monitored for disease to assess efficiency of PML-RARa silencing.